Cap-dependent endonuclease inhibitors

ABSTRACT

Provided is a compound of Formula (I) below, or a pharmaceutically acceptable salt, metabolite, or prodrug thereof: 
     
       
         
         
             
             
         
       
     
     wherein: A 1  is CR 4  or N; A 2  is CR 5 R 6  or NR 7 ; A 3  is CR 5 ′R 6 ′ or NR 7 ′; each of R 1 , R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 5 , R 5 ′, R 6 , R 6 ′, R 7 , and R 7 ′, independently, is hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, amino, formyl, nitro, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  alkoxy, C 2-6  alkenyloxy, C 1-6  alkylcarbonyl, C 1-6  alkyloxycarbonyl, C 1-6  alkylamine, C 3-20  carbocyclyl, or C 3-20  heterocyclyl; or R 5  and R 6 , R 5 ′ and R 6 ′, or R 5  and R 5 ′, together with the adjacent atom to which they are each attached, form C 3-10  carbocyclyl or C 3-10  heterocyclyl. Further provided are a method of using the above-described compound, or the pharmaceutically acceptable salt, metabolite, or prodrug thereof for treating influenza and a pharmaceutical composition containing same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority of United States Provisional PatentApplication No. 62/620,065, filed on Jan. 22, 2018.

TECHNICAL FIELD

The present disclosure is related to heterocyclic compounds that havecap-dependent endonuclease inhibitory activity, prodrugs thereof, andthe use thereof for to treating influenza.

BACKGROUND

The RNA polymerase of influenza viruses contains a cap-dependentendonuclease domain that cleaves host mRNAs to produce capped RNAfragments to serve as primers for initiating viral mRNA synthesis.

Translation of viral mRNAs by host ribosomes requires that the viralmRNAs be 5′-capped. This is achieved in cells infected with influenzaviruses by a “cap-snatching” mechanism in which the cap-dependentendonuclease cleaves 5′-caps from host mRNAs, which are then utilized astranscription primers (10-13 nucleotides). These capped RNA primers areused for synthesizing mRNAs encoding viral proteins.

Inhibiting the activity of cap-dependent endonuclease results insuppression of virus proliferation. As such, the cap-dependentendonuclease is a potential biological target for identifying effectiveanti-influenza agents.

Various heterocyclic compounds have been used as cap-dependentendonuclease inhibitors. Yet, conventional heterocyclic compoundsexhibit poor pharmacological properties, e.g., poor efficacy, lowsolubility, and poor bioavailability, thereby rendering them impracticalfor use as therapeutics for treating influenza.

There is a need to develop new cap-dependent endonuclease inhibitors fortreating influenza that do not suffer from the above-describeddrawbacks.

SUMMARY

The present disclosure relates to heterocyclic compounds ascap-dependent endonuclease inhibitors for treating influenza.Unexpectedly, these compounds demonstrate high potency in inhibiting theactivity of cap-dependent endonuclease.

An aspect of this disclosure is drawn to the compounds of Formula (I)below, or pharmaceutically acceptable salts, metabolites, or prodrugsthereof:

In this formula, R₁ is hydrogen, deuterium, halogen, cyano, hydroxyl,carboxyl, amino, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy,C₁₋₆ alkylamine, C₃₋₂₀ carbocyclyl or C₃₋₂₀ heterocyclyl; each of R₂,R₂′, R₃, and R₃′, independently, is hydrogen, deuterium, halogen, cyano,hydroxyl, carboxyl, amino, formyl, nitro, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₂₋₆ alkenyloxy, C₁₋₆ alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆ alkylamine, C₃₋₂₀ carbocyclyl, or C₃₋₂₀heterocyclyl; A₁ is CR₄ or N; A₂ is CR₅R₆ or NR₇; A₃ is CR₅′R₆′ or NR₇′;R₄ is hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, amino,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₃₋₂₀ carbocyclyl,or C₃₋₂₀ heterocyclyl; and each of R₅, R₅, R₆, R₆, R₇, and R₇,independently, is hydrogen, deuterium, halogen, cyano, hydroxyl,carboxyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂-6 alkynyl, C₁₋₆ alkoxy, C₃₋₂₀carbocyclyl, or C₃₋₂₀ heterocyclyl; or R₅ and R₆, R₅′ and R₆′, or R₅ andR₅′, together with the adjacent atom to which they are each attached,form C₃₋₁₀ carbocyclyl or C₃₋₁₀ heterocyclyl. Of note, each of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₂₋₆ alkenyloxy, C₁₋₆alkylcarbonyl, C₁₋₆ alkyloxycarbonyl, C₁₋₆ alkylamine, C₃₋₁₀carbocyclyl, C₃₋₁₀ heterocyclyl, C₃₋₂₀ carbocyclyl, and C₃₋₂₀heterocyclyl is to optionally substituted with 1 to 5 moieties ofdeuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₁₋₆ alkyl(C₃₋₁₀ carbocyclyl), C₁₋₆alkyl(C₃₋₁₀ heterocyclyl), C₁₋₆ alkoxy(C₃₋₁₀ carbocyclyl), C₁₋₆alkoxy(C₃₋₁₀ heterocyclyl), C₃₋₁₀ carbocyclyl, or C₃₋₁₀ heterocyclyl.

The compounds, salts, metabolites, or prodrugs described above includethe is compounds themselves, as well as their polymorphs, stereoisomersand solvates, if applicable. A salt, for example, can be formed betweenan anion and a positively charged group (e.g., amino) on a compoundhaving the above formula. Suitable anions include chloride, bromide,iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate,trifluoroacetate, acetate, malate, tosylate, tartrate, fumurate,glutamate, glucuronate, lactate, glutarate, and maleate. Likewise, asalt can also be formed between a cation and a negatively charged group(e.g., carboxylate) on a compound also having the above formula.Suitable cations include sodium ions, potassium ions, magnesium ions,calcium ions, and an ammonium cation such as a tetramethylammonium ion.The compounds also include those salts containing quaternary nitrogenatoms. For calculation simplicity, unless otherwise stated, the weightof a compound mentioned herein refers to that of the free base form ofthat compound.

Examples of prodrugs include esters and other pharmaceuticallyacceptable derivatives, which, upon administration to a subject, arecapable of providing active compounds. Typically, a prodrug of thisdisclosure has the following formula:

in which G is a group for forming a prodrug, which can be converted to acompound of Formula (I) in physiological conditions. Examples of Ginclude, but are not limited to, —C(R₉R₉′)—O—CO—R₁₀,—C(R₉R₉′)—O—CO—O—R₁₀, —C(R₉R₉′)—NR₁₁—C(═O)—CO—O—R₁₀,—C(R₉R₉′)—O—CO—C(R₉R₉′)—NR₁₁—CO—O—R₁₀, —C(R₉R₉′)—C(R₉R₉′)—O—CO—R₁₀,—C(R₉R₉′)—R₁₀, —C(═O)—O—R₁₀, —C(═O)—R₁₀, —C(═O)—O-alkylene-O—R₁₀,—C(═O)—NR₁₀R₁₁, and —P(═O)(R₁₂R₁₃), in which each of R₉, R₉′, and R₁₁,independently, is hydrogen or C₁₋₈ alkyl; R₁₀ is C₁₋₈ alkyl, C₃₋₁₀carbocyclyl, or C₃₋₁₀ heterocyclyl; R₁₂ is C₁₋₈ alkoxy; and R₁₃ is C₁₋₈alkoxy or C₁₋₈ alkylamine. A₁, A₂, A₃, R₁, R₂, R₂′, R₃, and R₃′ have thesame definition as in Formula (I).

A solvate refers to a complex formed between an active compound and apharmaceutically acceptable solvent. Examples of pharmaceuticallyacceptable solvents include water, ethanol, isopropanol, ethyl acetate,acetic acid, and ethanolamine.

Another aspect of this disclosure is a pharmaceutical compositioncontaining a compound, salt, metabolite, or prodrug described above andone or more pharmaceutically acceptable ingredients. The pharmaceuticalacceptable ingredients are diluents, disintegrants, binders, lubricants,glidants, surfactants, or a combination thereof. The pharmaceuticalcomposition can be used for treating influenza.

This disclosure also encompasses use of one or more of theabove-described compounds of Formula (I), as well as their salts,metabolites or prodrugs, for the manufacture of a medicament fortreating influenza.

Still another aspect of this disclosure is a method of preparing acompound of Formula (I), or a pharmaceutically acceptable salt,metabolite, or prodrug thereof.

A further aspect of this disclosure is a method for treating influenzaassociated to with cap-dependent endonuclease. The method includesadministering to a subject in need thereof an effective amount of one ormore of the compounds, salts, metabolites or prodrugs described above.

The term “treating” or “treatment” refers to administering one or moreof the compounds, salts, metabolites or prodrugs to a subject, who hasan above-described disease, i.e., influenza, a symptom of such adisease, or a predisposition toward such a disease, with the purpose toconfer a therapeutic effect, e.g., to cure, relieve, alter, affect,ameliorate, or prevent the above-described disease, the symptom thereof,or the predisposition toward it. “An effective amount” refers to theamount of an active compound, salt, metabolite, or prodrug that isrequired to confer the therapeutic effect. Effective doses will vary, asrecognized by those skilled in the art, depending on the types ofdisease treated, route of administration, excipient usage, and thepossibility of co-usage with other therapeutic treatment.

To practice the method of the present disclosure, a composition havingone or more of the above-described compounds, salts, metabolites orprodrugs can be administered parenterally, orally, nasally, rectally,topically, or buccally. The term “parenteral” as used herein refers tosubcutaneous, intracutaneous, intravenous, intraperitoneal,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional, or intracranial injection, aswell as any suitable infusion technique.

A sterile injectable composition can be a solution or suspension in anon-toxic parenterally acceptable diluent or solvent, such as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that canbe employed are mannitol, water, Ringer's solution, and isotonic sodiumchloride solution. In addition, fixed oils are conventionally employedas a solvent or suspending medium (e.g., synthetic mono- ordi-glycerides). Fatty acids, such as oleic acid and its glyceridederivatives, are useful in the preparation of injectables, as naturallypharmaceutically acceptable oils, such as olive oil and castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions can also contain a long chain alcohol diluent or dispersant,carboxymethyl cellulose, or similar dispersing agents. Other commonlyused surfactants such as Tweens and Spans or other similar emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms can also be used for the purpose of formulation.

A composition for oral administration can be any orally acceptabledosage form including capsules, tablets, emulsions and aqueoussuspensions, dispersions, and solutions. In the case of tablets,commonly used carriers include, among others, lactose and corn starch.Lubricating agents, such as magnesium stearate, are also typicallyadded. For oral administration in a capsule form, useful diluentsinclude lactose and dried corn starch. When aqueous suspensions oremulsions are administered orally, the active ingredient can besuspended or dissolved in an oily phase combined with emulsifying orsuspending agents. If desired, certain sweetening, flavoring, orcoloring agents can be added.

A nasal aerosol or inhalation composition can be prepared according totechniques well known in the art of pharmaceutical formulation. Forexample, such a composition can be prepared as a solution in saline,employing benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, fluorocarbons, and/or othersolubilizing or dispersing agents known in the art.

Of note, a composition having one or more of the above-describedcompounds, salts, metabolites and prodrugs can also be administered inthe form of suppositories for rectal administration.

The carrier in the pharmaceutical composition must be “acceptable” inthe sense that it is compatible with the active ingredient of thecomposition (and preferably, capable of stabilizing the activeingredient) and not deleterious to the subject to be treated. One ormore solubilizing agents can be utilized as pharmaceutical excipientsfor delivery of an active 1,5-diphenyl-penta-1,4-dien-3-one compound.Examples of other carriers include colloidal silicon oxide, magnesiumstearate, cellulose, sodium lauryl sulfate, and D&C Yellow #10.

Details of the present disclosure and practice thereof are set forth inthe description below. Note that other features, objects, and advantagesof the disclosure will be apparent from the following detaileddescription of several embodiments, as well as from the appendingclaims.

DETAILED DESCRIPTION

Disclosed in detail are compounds of Formula (I) below orpharmaceutically acceptable salts, metabolites, or prodrugs thereof:

To reiterate, R₁ is hydrogen, deuterium, halogen, cyano, hydroxyl,carboxyl, amino, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy,C₁₋₆ alkylamine, C₃₋₂₀ carbocyclyl or C₃₋₂₀ heterocyclyl; each of R₂,R₂′, R₃, and R₃′, independently, is hydrogen, deuterium, halogen, cyano,hydroxyl, carboxyl, amino, formyl, nitro, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₂₋₆ alkenyloxy, C₁₋₆ alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆ alkylamine, C₃₋₂₀ carbocyclyl or C₃₋₂₀heterocyclyl; A₁ is CR₄ or N; A₂ is CR₅R₆ or NR₇; A₃ is CR₅′R₆′ or NR₇′;R₄ is hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, amino,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₃₋₂₀ carbocyclyl,or C₃₋₂₀ heterocyclyl; and each of R₅, R₅′, R₆, R₆′, R₇, and R₇′,independently, is hydrogen, deuterium, halogen, cyano, hydroxyl,carboxyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₃₋₂₀carbocyclyl, or C₃₋₂₀ heterocyclyl; or R₅ and R₆, R₅′ and R₆′, or R₅ andR₅′, together with the adjacent atom to which they are each attached,form C₃₋₁₀ carbocyclyl or C₃₋₁₀ heterocyclyl. Note that each of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₂₋₆ alkenyloxy, C₁₋₆alkylcarbonyl, C₁₋₆ alkyloxycarbonyl, C₁₋₆ alkylamine, C₃₋₁₀carbocyclyl, C₃₋₁₀ heterocyclyl, C₃₋₂₀ carbocyclyl, and C₃₋₂₀heterocyclyl is optionally substituted with 1 to 5 moieties ofdeuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₁₋₆ alkyl(C₃₋₁₀ carbocyclyl), C₁₋₆alkyl(C₃₋₁₀ heterocyclyl), C₁₋₆ alkoxy(C₃₋₁₀ carbocyclyl), C₁₋₆alkoxy(C₃₋₁₀ heterocyclyl), C₃₋₁₀ carbocyclyl, or C₃₋₁₀ heterocyclyl.

The term “halogen” herein refers to a fluoro, chloro, bromo, or iodogroup. The term “hydroxyl” refers to an —OH group. The term “cyano”refers to a —CN group. The term “amino” refers to an —NH₂ group. Theterm “nitro” refers to an —NO₂ group. The term “carboxyl” refers to a—COOH group.

The term “C₁₋₆ alkyl” (alone or in combination with another term) refersto a straight- or branched-chain saturated hydrocarbyl substituentcontaining 1 to 6 (e.g., 1 to 4) carbon atoms. Examples of C₁₋₆ alkylinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, and the like. The term “C₂₋₆ alkenyl”(alone or in combination with another term) refers to a straight- orbranched-chain hydrocarbyl substituent containing 2 to 6 (e.g., 2 to 4)carbon atoms and one or more double bonds. Examples of C₂₋₆ alkenylinclude vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl,prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, and the like.The term “C₂₋₆ alkynyl” (alone or in combination with another term)refers to a straight- or branched-chain hydrocarbyl substituentcontaining 2 to 6 (e.g., 2 to 4) carbon atoms and one or more triplebonds. Examples of C₂₋₆ alkynyl include ethynyl, propynyl, butynyl,pentynyl, and the like.

The term “C₁₋₆ alkoxy” (alone or in combination with another term)refers to the group —OR wherein R is C₁₋₆ alkyl. Examples of C₁₋₆ alkoxyinclude methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy,sec-butoxy, and tert-butoxy.

The term “C₁₋₆ alkylamine” (alone or in combination with another term)refers to the group —NHR wherein R is C₁₋₆ alkyl. Examples of C₁₋₆alkylamine include methylamino, ethylamino, and isopropylamino.

The term “C₃₋₂₀ carbocyclyl” (alone or in combination with another term)refers to a saturated cyclic (i.e., “cycloalkyl”), partially saturatedcyclic (i.e., “cycloalkenyl”), or completely unsaturated (i.e., “aryl”)hydrocarbyl substituent containing from 3 to 20 carbon ring atoms (e.g.,3 to 10, C₃₋₁₀ carbocyclyl; 3 to 8, C₃₋₈ carbocyclyl; and 5 to 6, C₅₋₆carbocyclyl).

The term “cycloalkyl” (alone or in combination with another term) hereinrefers to a saturated cyclic hydrocarbyl substituent containing from 3to 20 carbon ring atoms. A cycloalkyl can be a single carbon ring, whichtypically contains from 3 to 10 carbon ring atoms, more typically from 3to 8 ring atoms, and even more typically 5 to 6 ring atoms. Examples ofsingle-ring cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl. Acycloalkyl can alternatively be a polycyclic ring. The term“cycloalkenyl” (alone or in combination with another term) refers to apartially saturated cyclic hydrocarbyl substituent containing from 3 to20 carbon ring atoms. A cycloalkenyl may be a single carbon ring, whichtypically contains from 3 to 10 carbon ring atoms, more typically from 3to 6 ring atoms, and even more typically 5 to 6 ring atoms. Examples ofsingle-ring cycloalkenyl include cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, cycloheptynyl, cyclooctynyl andcyclohexadienyl. A cycloalkenyl may alternatively be a polycyclic ring.The term “aryl” (alone or in combination with another term) refers to anaromatic carbocyclyl containing from 6 to 20 carbon ring atoms. An arylmay be monocyclic or polycyclic. In the case of a polycyclic aromaticring, only one ring of the polycyclic system is required to beunsaturated while the remaining ring(s) may be saturated, partiallysaturated or unsaturated. Examples of aryl include phenyl, naphthalenyl,indenyl, indanyl, and tetrahydronapthyl, fluorenyl, adamantyl.

A carbocyclyl can also be a polycyclic ring structure (i.e., containingtwo or more rings selected from “cycloalkyl”, “cycloalkenyl”, and“aryl”). Examples of a polycyclic carbocyclyl include bridged, fused,and spirocyclic carbocyclyls. In a bridged carbocyclyl, the rings shareat least two common non-adjacent atoms. In a fused-ring carbocyclylsystem, two or more rings may be fused together, such that the two ringsshare one common bond. Examples of fused-ring carbocyclyls includeindanyl, indenyl, tetrahydronaphthyl, and fluorenyl. A typicalfused-ring carbocyclyl is

The term “C₃₋₂₀ heterocyclyl” (alone or in combination with anotherterm) refers to a saturated (i.e., “heterocycloalkyl”), partiallysaturated (i.e., “heterocycloalkenyl”), or completely unsaturated (i.e.,“heteroaryl”) ring structure containing a total of 3 to 20 ring atoms,wherein at least one of the ring atoms is a heteroatom selected from thegroup consisting of O, N, and S. In one embodiment, heterocyclylcontains 1 to 4 (e.g., 1 to 2) heteroatoms of O, N, and S. The term“heterocycloalkyl” (alone or in combination with another term) refers toa saturated heterocyclyl. The term “heterocycloalkenyl” (alone or incombination with another term) refers to a partially saturatedheterocyclyl. The term “heteroaryl” (alone or in combination withanother term) refers to an aromatic heterocyclyl.

A heterocyclyl moiety may be a monocyclic structure, which typicallycontains from 3 to 10 ring atoms (i.e., C₃₋₁₀ heterocyclyl), moretypically from 3 to 8 ring atoms (i.e., C₃₋₈ heterocyclyl), and evenmore typically 5 to 6 ring atoms (i.e., C₅₋₆ heterocyclyl). Examples ofmonocyclic heterocyclyl include furanyl, tetrafuranyl, thiophenyl,pyrrolyl, imidazolyl, pyrrolinyl, pyrrolidinyl, imidazolyl,imidazolinyl, imidazolidinyl, pyridyl, dihydropyridyl,tetrahydropyridyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl,tetrahydropyridazinyl, pyrazolidinyl, triazolyl, tetrazolyl, oxazolyl,oxazolidinyl, isoxazolidinyl, isoxazolyl, thiazolyl, isothiazolyl,dihydrothiazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl,thiazolinyl, isothiazolinyl, thiazolidinyl, thianyl, thiazolidinyl,isothiazolidinyl, thiodiazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl,oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl, tetrahydropyranyl,thiopyranyl, tetrahydrothiopyranyl, pyridinyl, piperidyl, diazinyl,piperazinyl, triazinyl, isooxazolyl, oxazolyl, oxazinyl,dihydrooxazinyl, oxathiazinyl, oxadiazinyl, morpholinyl, morpholino,thiomorpholinyl, thiomorpholino, azepinyl, hexahydroazepinyl, oxepinyl,thiepinyl, diazepinyl, tetrahydrodiazepinyl, pyridonyl, pyrimidinyl,hexahydropyrimidinyl, dioxanyl, thiiranyl, oxetanyl, azetidinyl,dioxolanyl, dioxolyl, and oxabicycloheptanyl.

Alternatively, a heterocyclyl moiety can be a polycyclic structure.Examples of polycyclic heterocyclyl include bridged, fused, andspirocyclic heterocyclyls. In a bridged heterocyclyl, the rings share atleast two common non-adjacent atoms. In a fused-ring heterocyclyl, twoor more rings (e.g., dicyclic heterocyclyl or tricyclic heterocyclyl)may be fused together, such that the two rings share one common bond.Examples of fused-ring heterocyclyl containing two or three ringsinclude imidazopyrazinyl, imidazopyridinyl, imidazopyridazinyl,thiazolopyridinyl, indolizinyl, pyranopyrrolyl, purinyl, naphthyridinyl,pyridopyridinyl, pteridinyl, dihydrochromenyl, tetrahydroisoquinolinyl,indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, isoindazolyl,benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, quinolyl,isoquinolyl, cinnolinyl, benzodiazinyl, benzopyranyl, benzotriazolyl,benzimidazolyl, benzoxazolyl, benzoxadiazolyl, benzofuranyl,isobenzofuranyl, benzothienyl, benzoxazinyl, benzotriazolyl,benzisoxazinyl, benzisooxazolyl, thienopyridyl, thienopyrrolyl,thienopyrazolyl, thienopyrazinyl, furopyrrolyl, thienothienyl,imidazopyridyl, pyrazolopyridyl, thiazolopyridyl, pyrazolopyrimidinyl,pyrazolotrianizyl, pyridazolopyridyl, triazolopyridyl, imidazothiazolyl,pyrazinopyridazinyl, quinazolinyl, quinolyl, isoquinolyl,naphthyridinyl, dihydrothiazolopyrimidinyl, tetrahydroquinolyl,tetrahydroisoquinolyl, dihydrobenzofuryl, dihydrobenzoxazinyl,dihydrobenzimidazolyl, tetrahydrobenzothienyl, tetrahydrobenzofuryl,benzodioxolyl, benzodioxonyl, chromanyl, chromenyl, octahydrochromenyl,dihydrobenzodioxynyl, dihydrobenzooxezinyl, dihydrobenzodioxepinyl,dihydrothienodioxynyl, carbazolyl, acridinyl, xanthenyl, phenothiazinyl,phenoxathiinyl, phenoxazinyl, dibenzofuryl, imidazoquinolyl, andtetrahydrocarbazolyl. A typical fused-ring heterocyclyl is

Compounds of Formula (I) include the following four classes ofcompounds, i.e., Classes I-IV.

The Class I compounds feature that A₂ is NR₇ and A₃ is CR₅′R₆′.

The Class II compounds feature that A₂ is CR₅R₆ and A₃ is NR₇′.

The Class III compounds feature that A₂ is CR₅R₆ and A₃ is CR₅′R₆′. Inthis class, R₅ and R₅′, together with the adjacent atom to which theyare each attached, can form C₃₋₁₀ carbocyclyl or C₃₋₁₀ heterocyclyl.

The Class IV compounds feature that A₂ is NR₇ and A₃ is NR₇.

Referring back to Formula (I), R₁ is typically hydrogen, deuterium,cyano, halogen, hydroxyl, C₁₋₆ alkyl, or C₁₋₆ alkoxy. For example, R₁ ishydrogen, deuterium or C₁₋₆ alkyl. An exemplary compound of Formula (I)has R₁ being hydrogen.

On the other hand, each of R₄, R₅, R₅′, R₆, and R₆′, independently, istypically hydrogen, deuterium, halogen, cyano, hydroxyl, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₃₋₂₀ carbocyclyl, or C₃₋₂₀ heterocyclyl; andeach of R₇ and R₇′, independently, is typically hydrogen, deuterium,carboxyl, C₁₋₆ alkyl, C₃₋₂₀ carbocyclyl, or C₃₋₂₀ heterocyclyl. Forexample, each of R₇ and R₇′, independently, is C₁₋₆ alkyl, C₃₋₂₀carbocyclyl, or C₃₋₂₀ heterocyclyl, each of C₁₋₆ alkyl, C₃₋₂₀carbocyclyl, and C₃₋₂₀ heterocyclyl being optionally substituted with 1to 3 C₃₋₈ carbocyclyl or C₃₋₈ heterocyclyl. Other exemplary compounds ofFormula (I) each have R₇ and R₇′, independently, being

in which each of W₁ and W₂, independently, is C₃₋₈ carbocyclyl or C₃₋₈heterocyclyl; Y is O, S, SO, SO₂, or CH₂; R₈ is hydrogen, deuterium,halogen, hydroxyl, C₁₋₆ alkyl, or C₁₋₆ alkoxy, C₁₋₆ alkyl or C₁₋₆ alkoxybeing optionally substituted with 1 to 5 deuterium, halogen or hydroxylgroups; m is an integer of 1 to 5; n is an integer of 0 to 2; p is aninteger of 0 to 2; and the star (*) indicates a chiral center. In oneembodiment, each of R₇ and R₇′, independently, is

in which m is 1, 2, or 3. In one embodiment, each of R₇ and R₇′ is

in which m is 1, 2, or 3; each of R₁₄, R₁₅ and R₁₆, independently, ishydrogen or deuterium.

In one embodiment, compounds of Formula (I) each have A₂ being NR₇ andA₃ being CR₅′R₆′, in which each of R₅′ and R₆′, independently, ishydrogen, deuterium, halogen, cyano, hydroxyl, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₁₋₆ alkoxy, C₃₋₂₀ carbocyclyl, or C₃₋₂₀ heterocyclyl; and R₇ ishydrogen, deuterium, carboxyl, C₁₋₆ alkyl, C₃₋₂₀ carbocyclyl, or C₃₋₂₀heterocyclyl. In one embodiment, R₇ is C₁₋₆ alkyl, C₃₋₂₀ carbocyclyl, orC₃₋₂₀ heterocyclyl, each of C₁₋₆ alkyl, C₃₋₂₀ carbocyclyl, and C₃₋₂₀heterocyclyl being optionally substituted with 1 to 3 C₃₋₈ carbocyclylor C₃₋₈ heterocyclyl. In another embodiment, R₇ is

in which each variable is defined as set forth above. For example, R₇ is

in which m is 1, 2, or 3.

In another embodiment, compounds of Formula (I) each have A₂ being NR₇and A₃ being CR₅′R₆′, in which R₁ is hydrogen, deuterium, halogen, orC₁₋₆ alkyl; each of R₂, R₂′, R₃, and R₃′, independently, is hydrogen,deuterium, halogen, cyano, hydroxyl, carboxyl, amino, formyl, nitro,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₂₋₆ alkenyloxy,C₁₋₆ alkylcarbonyl, C₁₋₆ alkyloxycarbonyl, C₁₋₆ alkylamine, C₃₋₂₀carbocyclyl or C₃₋₂₀ heterocyclyl; each of R₅′ and R₆′, independently,is hydrogen, deuterium, halogen, C₁₋₆ alkyl, or C₂₋₆ alkenyl; and R₇ ishydrogen, deuterium, carboxyl, C₁₋₆ alkyl, C₃₋₂₀ carbocyclyl, or C₃₋₂₀heterocyclyl. In another embodiment, R₇ is C₁₋₆ alkyl, C₃₋₂₀carbocyclyl, or C₃₋₂₀ heterocyclyl, each of C₁₋₆ alkyl, C₃₋₂₀carbocyclyl, and C₃₋₂₀ heterocyclyl being optionally substituted with 1to 3 C₃₋₈ carbocyclyl or C₃₋₈ heterocyclyl. Exemplary compounds in thisembodiment each have R₇ being

in which each variable is defined as set forth above. Examples of R₇include, but are not limited to,

in which m is 1, 2, or 3.

In a further embodiment of compounds of Formula (I), A₁ is CH or N; A₂is NR₇; A₃ is CR₅′R₆′; R₁ is hydrogen, deuterium or C₁₋₆ alkyl; each ofR₂, R₂′, R₃, and R₃′, independently, is hydrogen, deuterium, halogen,cyano, hydroxyl, carboxyl, amino, formyl, nitro, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₂₋₆ alkenyloxy, C₁₋₆ alkylcarbonyl,C₁₋₆ alkyloxycarbonyl, C₁₋₆ alkylamine, C₃₋₂₀ carbocyclyl or C₃₋₂₀heterocyclyl; R₅ is hydrogen; R₆ is hydrogen, deuterium, C₁₋₆ alkyl, orC₂₋₆ alkenyl; and R₇ is

In one embodiment, the compounds of Formula (I) can be represented bythe following formulas, i.e., Formula (II) and Formula (III):

in which R₁, R₂, R₂′, R₃, R₃′, R₄, R₅′, R₆′, and R₇ are defined asabove.

Each of the above-listed exemplary compounds of Formula (I) can beconverted into a prodrug thereof having the following formula:

In this formula, G can be —C(R₉R₉′)—O—CO—R₁₀, —C(R₉R₉′)—O—CO—O—R₁₀,—C(R₉R₉′)—NR₁₁—C(═O)—CO—O—R₁₀, —C(R₉R₉′)—O—CO—C(R₉R₉′)—NR₁₁—CO—O—R₁₀,—C(R₉R₉′)—C(R₉R₉′)—O—CO—R₁₀, —C(R₉R₉′)—R₁₀, —C(═O)—O—R₁₀, —C(═O)—R₁₀,—C(═O)—O-alkylene-O—R₁₀, —C(═O)—NR₁₀R₁₁, or —P(═O)(R₁₂R₁₃), in whicheach of R₉, R₉′, and R₁₁, independently, is hydrogen or C₁₋₈ alkyl; R₁₀is C₁₋₈ alkyl, C₃₋₁₀ carbocyclyl, or C₃₋₁₀ heterocyclyl; R₁₂ is C₁₋₈alkoxy; and R₁₃ is C₁₋₈ alkoxy or C₁₋₈ alkylamine. An exemplary G is oneof the following groups:

The —OG group is converted into an —OH group in the formula (I) by adecomposition reaction caused by drug-metabolizing enzymes, hydrolases,gastric acids, enterobacteria, etc. under physiological conditions invivo. The prodrug becomes a parent compound having an inhibitoryactivity on cap-dependent endonuclease in vivo after administrationthereof. In this disclosure, the prodrugs demonstrate betterbioavailability and higher maximum concentration (C_(max)) than theparent compounds.

Compounds of this disclosure that have chiral centers may exist asstereoisomers. Stereoisomers of the compounds of Formula (I) can includecis and trans isomers, optical isomers such as (R) and (S) enantiomers,diastereomers, geometric isomers, rotational isomers, atropisomers,conformational isomers, and tautomers of the compounds, includingcompounds exhibiting more than one type of isomerism and mixturesthereof (such as racemates and diastereomers). All such isomeric formsare contemplated. In addition, the compounds of Formula (I) in thepresent disclosure may exhibit the phenomena of tautomerism.

Of note, the compounds of Formula (I) with enriched enantiopurity canhave an enantiomeric excess of 90% or higher (e.g., ≥95% and ≥99%).

Also within this disclosure is a pharmaceutical composition containingone or more of the above-described compounds, salts, metabolites orprodrugs for treating influenza.

Further covered by this disclosure is a method for treating influenza,the method including administering to a subject in need thereof aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, metabolite or prodrug thereof.

Still within the scope of this disclosure is a method of preparing acompound of Formula (I) below, or a pharmaceutically acceptable salt,metabolite, or prodrug thereof,

wherein the method includes the following steps: (i) providing analdehyde

P being a protecting group; (ii) reacting the aldehyde with a carbonylcompound

to afford a first intermediate

(iii) reacting the first intermediate with a hydrazine to afford asecond intermediate

and (iv) converting the second intermediate to a compound of Formula(I), or a pharmaceutically acceptable salt or prodrug thereof, in whichA₁ is CR₄, A₂ is NR₇, and A₃ is CR₅′R₆′; R₁ is hydrogen, deuterium,halogen, cyano, hydroxyl, carboxyl, amino, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylamine, C₃₋₂₀ carbocyclyl, or C₃₋₂₀heterocyclyl; each of R₂, R₂′, R₃, and R₃′, independently, is hydrogen,deuterium, halogen, cyano, hydroxyl, carboxyl, amino, formyl, nitro,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₂₋₆ alkenyloxy,C₁₋₆ alkylcarbonyl, C₁₋₆ alkyloxycarbonyl, C₁₋₆ alkylamine, C₃₋₂₀carbocyclyl, or C₃₋₂₀ heterocyclyl; R₄ is hydrogen, deuterium, halogen,cyano, hydroxyl, carboxyl, amino, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₃₋₂₀ carbocyclyl, or C₃₋₂₀ heterocyclyl; R₅ is H;and each of R₆ and R₇, independently, is hydrogen, deuterium, halogen,cyano, hydroxyl, carboxyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₃₋₂₀ carbocyclyl, or C₃₋₂₀ heterocyclyl. Again, each of theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₂₋₆ alkenyloxy,C₁₋₆ alkylcarbonyl, C₁₋₆ alkyloxycarbonyl, C₁₋₆ alkylamine, C₃₋₂₀carbocyclyl, and C₃₋₂₀ heterocyclyl is optionally substituted with 1 to5 moieties of deuterium, halogen, hydroxyl, cyano, amino, nitro,carboxyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₁₋₆ alkyl(C₃₋₁₀carbocyclyl), C₁₋₆ alkyl(C₃₋₁₀ heterocyclyl), C₁₋₆ alkoxy(C₃₋₁₀carbocyclyl), C₁₋₆ alkoxy(C₃₋₁₀ heterocyclyl), C₃₋₁₀ carbocyclyl, orC₃₋₁₀ heterocyclyl.

The compounds of Formula (I) described above can be initially screenedusing in vitro assays, e.g., the cytopathic effect reduction assaydescribed in EXAMPLE 2 below, for their potency in inhibiting theactivity of cap-dependent endonuclease. They can be subsequentlyevaluated using in vivo assays, e.g., the influenza A mouse model studydescribed in EXAMPLE 3 below. The selected compounds can be furthertested to verify their efficacy in treating influenza. Based on theresults, appropriate dosage ranges and administration routes can beinvestigated and determined.

Without further elaboration, it is believed that one skilled in the artcan, based on the above description, utilize the present disclosure toits fullest extent. The following specific examples, i.e., EXAMPLES 1-3,are therefore to be construed as merely illustrative, and not limitativeof the remainder of the disclosure in any way whatsoever.

Among the specific examples, EXAMPLE 1 sets forth the procedures forpreparing certain intermediates, exemplary compounds of Formula (I), andexemplary prodrugs of compounds of Formula (I), as well as theanalytical data for the compounds thus prepared; and EXAMPLES 2 and 3set forth the protocols for testing these compounds.

Shown in the table below are the structures of 39 exemplary compounds ofFormula (I).

Compound 1

Compound 2

Compound 3

Compound 4

Compound 5

Compound 6

Compound 7

Compound 8

Compound 9

Compound 10

Compound 11

Compound 12

Compound 13

Compound 14

Compound 15

Compound 16

Compound 17

Compound 18

Compound 19

Compound 20

Compound 21

Compound 22

Compound 23

Compound 24

Compound 25

Compound 26

Compound 27

Compound 28

Compound 29

Compound 30

Compound 31

Compound 32

Compound 33

Compound 34

Compound 35

Compound 36

Compound 37

Compound 38

Compound 39

Described below are the procedures used to synthesize theabove-described 39 exemplary compounds.

All the reagents and solvents were purchased from commercial sources andused without further purification unless otherwise indication. All thereactions were carried out under dry nitrogen or argon atmosphere andmonitored by thin layer chromatography (TLC) using Merck Silica gel 60F₂₅₄ glass-backed plate. Column chromatography was performed by MerckSilica gel 60 (0.040-0.063 mm, 230-400 mesh). ¹H NMR and ¹³C NMR spectrawere measured by Varian Mercury-300 and Varian Bruker AVIII-500spectrometers, and the chemical shifts (6) were reported in parts permillion (ppm) relative to the resonance of the solvent peak.Multiplicities are reported with the following abbreviations: s(singlet), d (doublet), t (triplet), q (quartet), quin (quintet), m(multiplet), or br (broad). Low-resolution mass spectra were measured byHP Hewlett Packard 1100 series.

The following scheme was followed for synthesizing certain compounds ofFormula (I).

Example 1: Preparation and Characterization of Compounds 1-39 Synthesisand Characterization of Compound 11-(1-Fluoro-5,11-dihydro-10-thia-dibenzo[a,d]cyclohepten-5-yl)-5-hydroxy-3,3-cyclopropyl-2,3-dihydro-1H-pyrido[1,2-b]pyridazine-4,6-dione(Compound 1)

Compound I-3 was first prepared from commercially available3-benzyloxy-4-oxo-4H-pyran-2-carbaldehyde via intermediates I-1 and 1-2,following the scheme shown below:

Pyrrolidine (30.9 g, 434 mmole) was added to the solution of3-(benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde (100 g, 434 mmole) andcyclopropanecarbaldehyde (91.3 g, 1.30 mmole) in solvent DMSO (1 L), andthe mixture was stirred at 50° C. for 23 to 24 hours and then cooled toroom temperature. The resulting mixture was dissolved in CH₂Cl₂ (1.0 L),washed with 1N HCl_((aq)) (1.0 L) and a saturated aqueous solution ofNaHCO₃ (1.0 L), followed by a saturated brine (1.0 L). The organic phasewas separated and dried over anhydrous MgSO₄. The solvent was removedunder reduced pressure to obtain residue (133 g). The residue thusobtained was dissolved in EtOAc (1.0 L), washed with a saturated aqueoussolution of NaHCO₃ (1.0 L), followed by a saturated aqueous solution ofNaCl (1.0 L), and dried over anhydrous MgSO₄, and then the solvent wasevaporated under reduced pressure to form a black crude material (106g). The resulting crude material was purified by column chromatography(hexane/EtOAc=7/3) and then recrystallization with (hexane/EtOAc=1/1) toafford compound I-1 as a yellow-green solid (87 g, 66%).

NH₂NHCOCF₃ (8.23 g, 64 mmole) was added to the solution of compound I-1(9.65 g, 32 mmole) in MeOH (145 mL) and H₂O (73 mL). The reactionmixture was stirred at 50° C. for 20 hours. After cooling to roomtemperature, the solvent were removed under reduced pressure. The solidresidue was dissolved in CH₂Cl₂ (500 mL×3) and washed with a saturatedaqueous solution of NaCl (200 mL). The organic phase was separated anddried over anhydrous MgSO₄. The solvent was removed under reducedpressure and the crude product was washed with MTBE (250 mL) to affordthe compound I-2 (8.6 g, 90%).

The NaBH₄ (1.05 g, 27.8 mmole) was added slowly to a solution ofcompound I-2 (4.32 g, 13.9 mmole) in MeOH (38 mL) at 0° C. The reactionmixture was stirred at room temperature for 1 hour. After 1 hour, H₂O(10 mL) was added to the reaction solution, and the solvent was removedunder reduced pressure. The solid residue was dissolved in CH₂Cl₂ (250mL×3) and washed with a saturated aqueous solution of NaCl (100 mL). Theorganic phase was separated and dried over anhydrous MgSO₄, and removedunder reduced pressure to obtain the crude product (4.47 g).

Compound I-4 was prepared from commercially available9-fluoro-11H-10-thia-dibenzo[a,d]cyclohepten-5-one via the route shownbelow:

To a solution of 9-fluoro-11H-10-thia-dibenzo[a,d]cyclohepten-5-one (1.4g, 6.1 mmole), NaBH₄ (0.28 g, 7.3 mmole) was stirred in THF/MeOH (1:1,20 mL) at 0° C., then allowed to return to room temperature for 1 hour.After reaction completed, then quenched with H₂O and extracted withCH₂Cl₂, the organic layer was dried with Na₂SO₄ and concentrated underreduced pressure to obtain 1.4 g of crude residue, which was used in thenext step without being purified. Then, the crude residue and SOCl₂(0.88 ml, 12.2 mmole) were stirred in CH₂Cl₂ (10 mL) at 0° C., and thenallowed to return to room temperature. After reaction completed and thenconcentrated under reduced pressure, crude compound I-4 was obtainedwhich was directly used without being purified.

Compound 1 was prepared via intermediates I-3 to I-6 as follows. Asolution of compound I-3 (150 mg, 0.5 mmole), cesium carbonate (491 mg,1.5 mmole) and compound I-4 (265 mg, 1.0 mmole) was stirred in ACN (6ml) at 50° C. for 3 hours. CHCl₂ dilute, H₂O wash, the organic layerNa₂SO₄ dried, concentrated under reduced pressure, the residue waspurified by silica gel chromatography eluting with CH₂Cl₂:MeOH=39:1 toafford compound I-5 (92 mg, 0.17 mmole, yield: 34%).

To a solution of compound I-5 (92 mg, 0.17 mmole), Dess-Martinperiodinane (1.09 g, 2.56 mmole) and NaHCO₃ (725 mg) were stirred in ACN(50 ml) at 75° C. for 1 hour. The reaction was washed with H₂O, and theorganic layer Na₂SO₄ was dried and concentrated under reduced pressure.The residue was purified by silica gel chromatography eluting withCH₂Cl₂:MeOH=39:1 to afford compound I-6 (60 mg, 0.11 mmole, yield: 67%).

To a solution of compound I-6 (60 mg, 0.114 mmole) was dissolved in EA(20 ml) and CHCl₂ (10 ml), and Pd—C (35 mg) was added. The mixture wasstirred under hydrogen (1 atm) at room temperature for 1 hour. Thecatalyst was removed by filtrating through a pad of celite. The filtratewas concentrated under reduced pressure to give compound 1 (46 mg, 0.106mmole, yield: 93%). MS: m/z 435.1 (M+H)+; ¹H NMR (CDCl₃) δ7.31-6.89 (m,6H), 6.66-6.64 (m, 1H), 6.57 (d, 1H), 5.83 (d, 1H), 5.42 (d, 1H), 5.02(s, 1H), 4.14 (d, 1H), 4.06 (d, 1H), 3.32 (br, 1H), 2.91 (d, 1H),1.88-1.86 (m, 1H), 1.70-1.68 (m, 1H), 0.99-0.96 (m, 1H), 0.84-0.79 (m,1H).

Synthesis and Characterization of Compounds 2-39

Each of Compounds 2-39 was similarly prepared following the scheme asset forth above and the protocols described in the preparation ofCompound 1.

Analytical data of compounds 2-39 are listed below.

Compound 2: MS: m/z 453.1 (M+H)⁺; ¹H NMR (CDCl₃) δ7.27 (d, 1H),7.08-7.00 (m, 4H), 6.80-6.78 (m, 1H), 6.63 (d, 1H), 5.83 (d, 1H), 5.50(dd, 1H), 5.23 (s, 1H), 4.15 (d, 1H), 4.06 (d, 1H), 2.91 (d, 1H), 2.43(br, 1H), 1.92-1.84 (m, 1H), 1.78-1.67 (m, 1H), 0.96-0.92 (m, 1H),0.86-0.81 (m, 1H).

Compound 3: MS: m/z 468.9 (M+H)⁺; ¹H NMR (CDCl₃) δ7.31-7.19 (m, 3H),7.07-6.96 (m, 2H), 6.79-6.74 (m, 1H), 6.62 (d, 1H), 5.89-5.81 (m, 2H),5.30 (s, 1H), 4.13 (d, 1H), 3.62 (d, 1H), 2.9 (d, 1H), 1.90-1.87 (m,1H), 1.72-1.67 (m, 1H), 0.94-0.80 (m, 2H).

Compound 4: MS: m/z 451.1 (M+H)⁺; ¹H NMR (CDCl₃) δ7.31-7.08 (m, 6H),6.80-6.78 (m, 1H), 6.65 (d, 1H), 5.83 (d, 1H), 5.71 (d, 1H), 5.21 (s,1H), 4.13 (d, 1H), 3.51 (d, 1H), 2.89 (d, 1H), 1.89-1.87 (m, 1H),1.71-1.69 (m, 1H), 0.97-0.83 (m, 2H).

Compound 5: MS: m/z 453.1 (M+H)⁺; ¹H NMR (CD₃OD) δ7.52-7.44 (m, 2H),7.22-7.18 (m, 1H), 7.08-7.03 (m, 1H), 6.99-6.93 (m, 1H), 6.85-6.83 (m,1H), 6.70-6.68 (m, 1H), 5.91 (d, 1H), 5.85 (d, 1H), 5.55 (s, 1H), 4.20(d, 1H), 3.79 (d, 1H), 2.97 (d, 1H), 1.98-1.85 (m, 1H), 1.64-1.48 (m,1H), 1.15-1.00 (m, 1H), 0.99-0.85 (m, 1H).

Compound 6: MS: m/z 465.1 (M+H)⁺; ¹H NMR (CDCl₃) δ7.31-7.10 (m, 4H),7.00 (d, 1H), 6.74-6.69 (m, 1H), 6.53 (d, 1H), 5.82 (d, 1H), 5.75 (d,1H), 5.23 (s, 1H), 4.13 (d, 1H), 3.61 (d, 1H), 2.90 (d, 1H), 2.25 (s,3H), 1.89 (br, 1H), 1.72-1.70 (m, 1H), 1.62-1.60 (m, 1H), 0.97-0.93 (m,1H), 0.85-0.82 (m, 1H).

Compound 7: MS: m/z 449.1 (M+H)⁺; ¹H NMR (CDCl₃) δ7.25-7.18 (m, 2H),7.09-6.92 (m, 3H), 6.70 (t, 1H), 6.52 (d, 1H), 5.84-5.74 (m, 2H), 5.23(s, 1H), 4.12 (d, 1H), 3.59 (d, 1H), 3.26 (br, 1H), 2.89 (d, 1H), 2.24(s, 3H), 1.90-1.86 (m, 1H), 1.71-1.65 (m, 1H), 0.99-0.92 (m, 1H),0.86-0.79 (m, 1H).

Compound 8: MS: m/z 435.1 (M+H)⁺; ¹H NMR (CDCl₃) δ7.29-7.18 (m, 2H),7.07-6.94 (m, 4H), 6.80-6.76 (m, 1H), 6.65 (d, 1H), 5.84 (d, 1H), 5.75(d, 1H), 5.21 (s, 1H), 4.15-4.01 (m, 1H), 3.50 (d, 1H), 2.91 (d, 1H),1.89-1.87 (m, 1H), 1.72-1.67 (m, 1H), 0.97-0.93 (m, 1H), 0.87-0.80 (m,1H).

Compound 9: MS: m/z 435.1 (M+H)⁺; ¹H NMR (DMSO-d₆) δ7.47-7.29 (m, 5H),7.04-7.00 (m, 1H), 6.88-6.74 (m, 1H), 6.75-6.64 (m, 1H), 5.83 (d, 1H),5.73 (d, 1H), 5.49 (s, 1H), 4.09-3.95 (m, 2H), 2.78 (d, 1H), 1.64-1.58(m, 1H), 1.21-1.13 (m, 1H), 0.71-0.60 (m, 1H), 0.58-0.45 (m, 1H).

Compound 10: MS: m/z 449.1 (M+H)⁺; 1H NMR (CD₃OD) δ7.47-7.45 (m, 1H),7.28-7.18 (m, 3H), 7.04-7.02 (m, 1H), 6.73-6.70 (m, 2H), 5.84 (d, 1H),5.58 (d, 1H), 5.49 (s, 1H), 4.18 (d, 2H), 2.98 (d, 1H), 2.24 (s, 3H),1.98-1.87 (m, 1H), 1.67-1.58 (m, 1H), 1.18-1.03 (m, 1H), 0.96-0.87 (m,1H).

Compound 11: MS: m/z 431.2 (M+H)⁺; 1H NMR (CDCl₃) δ7.36-7.23 (m, 5H),6.98 (d, 1H), 6.72-6.67 (m, 1H), 6.54 (d, 1H), 5.82 (d, 1H), 5.75 (d,1H), 5.23 (s, 1H), 4.12 (d, 1H), 3.66 (d, 1H), 2.90 (d, 1H), 2.23 (s,3H), 1.90-1.83 (m, 1H), 1.72-1.62 (m, 1H), 1.01-0.92 (m, 1H), 0.86-0.79(m, 1H).

Compound 12: MS: m/z 469.1 (M+H)⁺; ¹H NMR (CDCl₃) δ7.26-7.02 (m, 5H),6.76 (t, 1H), 6.63 (d, 1H), 5.89 (d, 1H), 5.51 (d, 1H), 5.32 (s, 1H),4.17 (d, 1H), 4.15 (d, 1H), 3.17 (br, 1H), 2.91 (d, 1H), 1.93-1.87 (m,1H), 1.72-1.67 (m, 1H), 1.00-0.81 (m, 2H).

Compound 13: MS: m/z 451.1 (M+H)⁺; 1H NMR (CDCl₃) δ7.43-7.15 (m, 6H),6.75 (t, 1H), 6.63 (d, 1H), 5.88 (d, 1H), 5.79 (d, 1H), 5.27 (s, 1H),4.12 (d, 1H), 3.68 (d, 1H), 3.43 (br, 1H), 2.90 (d, 1H), 1.91-1.87 (m,1H), 1.71-1.66 (m, 1H), 0.99-0.79 (m, 2H).

Compound 14: MS: m/z 469.1 (M+H)⁺; 1H NMR (CDCl₃) δ7.38-7.16 (m, 4H),6.94-6.88 (m, 1H), 6.83-6.76 (m, 1H), 6.50 (d, 1H), 5.72 (d, 1H), 5.75(d, 1H), 5.26 (s, 1H), 4.14 (d, 1H), 3.60 (d, 1H), 2.90 (d, 1H), 2.60(br, 1H), 1.90-1.88 (m, 1H), 1.71-1.69 (m, 1H), 0.96-0.81 (m, 2H).

Compound 15: MS: m/z 453.1 (M+H)⁺; 1H NMR (CD₃OD) δ7.48-7.24 (m, 2H),7.24-6.96 (m, 3H), 6.80-6.50 (m, 2H), 6.50-6.34 (m, 1H), 5.89 (d, 1H),5.14-5.00 (m, 2H), 4.06 (d, 1H), 2.83 (d, 1H), 2.10-1.96 (m, 1H),1.78-1.60 (m, 1H), 1.16-1.00 (m, 1H), 0.96-0.80 (m, 1H).

Compound 16: MS: m/z 467.1 (M+H)⁺; 1H NMR (CDCl₃) δ7.21 (d, 1H),7.10-7.00 (m, 3H), 6.72 (t, 1H), 6.51 (d, 1H), 5.82 (d, 1H), 5.51 (d,1H), 5.24 (s, 1H), 4.16-4.07 (m, 2H), 2.91 (d, 1H), 2.24 (s, 3H),2.03-1.66 (m, 3H), 0.99-0.81 (m, 2H).

Compound 17: MS: m/z 471.0 (M+H)⁺; ¹H NMR (DMSO-d₆) δ7.39-7.37 (m, 2H),7.21 (d, 1H), 7.09 (t, 1H), 6.93-6.86 (m, 1H), 6.79 (d, 1H), 5.72-5.68(m, 1H), 5.63 (s, 1H), 5.52 (d, 1H), 4.20 (d, 1H), 4.09 (d, 1H), 2.90(d, 1H), 1.79-1.67 (m, 1H), 1.36-1.31 (m, 1H), 0.90-0.70 (m, 2H).

Compound 18: MS: m/z 486.9 (M+H)⁺; ¹H NMR (CDCl₃) δ7.26-7.20 (m, 2H),7.12-6.96 (m, 2H), 6.76 (t, 1H), 6.60 (d, 1H), 5.90 (d, 1H), 5.56 (d,1H), 5.28 (s, 1H), 4.14 (d, 2H), 2.90 (d, 1H), 2.64 (br, 1H), 1.92-1.87(m, 1H), 1.73-1.67 (m, 1H), 0.97-0.80 (m, 2H).

Compound 19: MS: m/z 469.0 (M+H)⁺; 1H NMR (CDCl₃) δ7.34-7.26 (m, 2H),7.10-7.09 (m, 2H), 6.99 (d, 1H), 6.84-6.79 (m, 1H), 6.65 (d, 1H), 5.84(d, 1H), 5.49 (dd, 1H), 5.24 (s, 1H), 4.17 (d, 1H), 4.07 (d, 1H), 2.92(d, 1H), 1.93-1.88 (m, 1H), 1.75-1.68 (m, 1H), 1.02-0.95 (m, 1H),0.90-0.83 (m, 1H).

Compound 20: MS: m/z. 467.1 (M+H)⁺; 1H NMR (CDCl₃) δ7.28 (d, 1H),7.09-7.03 (m, 3H), 7.02-6.95 (m, 1H), 6.82-6.77 (m, 1H), 6.62 (d, 1H),5.85 (d, 1H), 5.53 (dd, 1H), 5.16 (s, 1H), 4.09 (d, 1H), 4.04 (d, 1H),2.96 (d, 1H), 2.13-2.09 (m, 1H), 2.05-1.96 (m, 1H), 1.06 (d, 3H),0.69-0.66 (m, 1H).

Compound 21: MS: m/z 467.0 (M+H)⁺; 1H NMR (CDCl₃) δ7.30-7.20 (m, 2H),7.14-6.78 (m, 4H), 6.65 (d, 0.4H), 6.57-6.52 (m, 0.6H), 5.94 (d, 0.6H),5.85 (d, 0.4H), 5.46-5.33 (m, 1H), 5.22 (s, 0.4H), 5.04 (s, 0.6H), 4.18(d, 0.6H), 4.06 (d, 0.4H), 3.14-3.02 (m, 1H), 1.87-1.74 (m, 1.4H),1.66-1.58 (m, 0.6H), 1.35-1.33 (m, 3H), 1.03-0.84 (m, 1.4H), 0.70-0.64(m, 0.6H).

Compound 22: MS: m/z. 480.1 (M+H)⁺; 1H NMR (CDCl₃) δ7.33-7.27 (m, 2H),7.16-6.96 (m, 3H), 6.91-6.79 (m, 1H), 6.64 (d, 0.5H), 6.57-6.53 (m,0.5H), 5.94 (d, 0.5H), 5.85 (d, 0.5H), 5.67 (dd, 0.5H), 5.37 (dd, 0.5H),5.30 (s, 0.5H), 5.13 (s, 0.5H), 4.16 (d, 0.5H), 4.04 (d, 0.5H),2.82-2.74 (m, 1H), 1.92-1.52 (m, 4H), 1.13-1.02 (m, 4H), 0.97-0.81 (m,1H).

Compound 23: MS: m/z 503.0 (M+H)⁺; ¹H NMR (CDCl₃) δ7.36-7.21 (m, 3H),6.99 (d, 1H), 6.78 (t, 1H), 6.62 (d, 1H), 5.88 (d, 1H), 5.58 (d, 1H),5.30 (s, 1H), 4.19-4.15 (m, 2H), 2.92 (d, 1H), 2.04-1.06 (m, 3H),0.96-0.85 (m, 2H).

Compound 24: MS: m/z 487.0 (M+H)⁺; 1H NMR (CDCl₃) δ7.36-7.23 (m, 2H),7.01-6.91 (m, 2H), 6.85-6.81 (m, 1H), 6.51 (d, 1H), 5.89 (d, 1H), 5.54(d, 1H), 5.31 (s, 1H), 4.18-4.14 (m, 2H), 2.92 (d, 1H), 2.17 (br, 1H),1.93-1.88 (m, 1H), 1.74-1.69 (m, 1H), 0.97-0.86 (m, 2H).

Compound 25: MS: m/z. 479.1 (M+H)⁺; 1H NMR (CDCl₃) δ7.33-7.31 (m, 1H),7.23-6.98 (m, 3H), 6.92-6.85 (m, 1H), 6.81-6.76 (m, 1H), 6.67 (d, 0.5H),6.60-6.55 (m, 0.5H), 5.92 (d, 0.5H), 5.90-5.78 (m, 1.5H), 5.49 (dd,0.5H), 5.37 (dd, 0.5H), 5.33-5.27 (m 2H), 5.21 (s, 0.5H), 5.09 (s,0.5H), 4.18 (d, 0.5H), 4.08 (d, 0.5H), 3.44-3.40 (m, 1H), 1.93-1.87 (m,1.5H), 1.78-1.74 (m, 0.5H), 1.12-1.07 (m, 0.5H), 0.98-0.90 (m, 1H),0.72-0.68 (m, 0.5H).

Compound 26: MS: m/z 485.0 (M+H)⁺; 1H NMR (CDCl₃) δ7.23 (d, 1H),7.15-7.07 (m, 2H), 6.70-6.83 (m, 2H), 6.57-6.52 (m, 0.5H), 6.51 (d,0.5H), 5.96 (d, 0.5H), 5.91 (d, 0.5H), 5.51 (d, 0.5H), 5.46 (d, 0.5H),5.29 (s, 0.5H), 5.11 (s, 0.5H), 4.24 (d, 0.5H), 4.15 (d, 0.5H),3.12-3.08 (m, 1H), 1.90-1.76 (m, 1.5H), 1.66-1.64 (m, 0.5H), 1.37-1.33(m, 3H), 1.05-0.89 (m, 1.5H), 0.72-0.66 (m, 0.5H).

Compound 27: MS: m/z 481.1 (M+H)⁺; 1H NMR (CDCl₃) δ7.23 (d, 1H),7.18-7.16 (m, 1H), 7.10-6.97 (m, 2.5H), 6.91-6.83 (m, 1H), 6.75-6.70 (m,0.5H), 6.60-6.53 (m, 1H), 5.96 (d, 0.5H), 5.84 (d, 0.5H), 5.48 (dd,0.5H), 5.35 (dd, 0.5H), 5.25 (s, 0.5H), 5.07 (s, 0.5H), 4.23 (d, 0.5H),4.16 (d, 0.5H), 3.12-3.03 (m, 1H), 2.34 (s, 1.5H), 2.25 (s, 1.5H),1.85-1.65 (m, 1.5H), 1.60-1.51 (m, 0.5H), 1.36-1.25 (m, 3H), 1.04-0.89(m, 1.5H), 0.70-0.67 (m, 0.5H).

Compound 28: MS: m/z. 467.1 (M+H)⁺; ¹H NMR (CDCl₃) δ7.14-7.02 (m, 4H),6.83-6.80 (m, 1H), 6.62 (d, 1H), 5.88 (s, 1H), 5.43 (dd, 1H), 5.18 (s,1H), 4.00 (d, 1H), 3.95 (d, 1H), 2.87 (d, 1H), 2.25 (s, 3H), 1.93-1.87(m, 1H), 1.64-1.57 (m, 1H), 0.87-0.80 (m, 1H), 0.67-0.60 (m, 1H).

Compound 29: MS: m/z 497.0 (M+H)⁺; 1H NMR (CDCl₃) δ7.56-7.54 (m, 2H),7.40-7.32 (m, 1H), 7.29-7.18 (m, 3H), 6.91-6.83 (m, 2H), 6.05-5.99 (m,1H), 5.96 (s, 1H), 5.81-5.79 (m, 1H), 4.22-4.19 (m, 1H), 3.60-3.56 (m,1H), 2.96-2.90 (m, 1H), 2.28 (br, 1H), 2.16-2.10 (m, 1H), 1.51-1.48 (m,1H), 0.97-0.83 (m, 2H).

Compound 30: MS: m/z. 485.0 (M+H)⁺; 1H NMR (CDCl₃) δ7.12-7.02 (m, 2H),6.98-6.92 (m, 1H), 6.86-6.79 (m, 1H), 6.48 (d, 1H), 5.89 (s, 1H), 5.41(dd, 1H), 5.30 (s, 1H), 4.09 (d, 1H), 3.98 (d, 1H), 2.87 (d, 1H), 2.25(s, 3H), 1.94-1.87 (m, 1H), 1.65-1.58 (m, 1H), 0.88-0.81 (m, 1H),0.66-0.63 (m, 1H).

Compound 31: MS: m/z. 481.1 (M+H)⁺; 1H NMR (CDCl₃) δ7.09-7.02 (m, 3H),6.77-6.72 (m, 1H), 6.51 (d, 1H), 5.87 (d, 1H), 5.45 (dd, 1H), 5.20 (s,1H), 4.08 (d, 1H), 3.96 (d, 1H), 2.87 (d, 1H), 2.21 (s, 3H), 2.19 (s,3H), 1.93-1.86 (m, 1H), 1.64-1.56 (m, 1H), 0.86-0.79 (m, 1H), 0.64-0.58(m, 1H).

Compound 32: MS: m/z 525.0 (M+H)⁺; 1H NMR (CDCl₃) δ7.31 (d, 1H),7.12-7.07 (m, 3H), 6.99-6.89 (m, 1H), 6.86-6.76 (m, 1H), 6.63-6.60 (m,1H), 5.86 (d, 1H), 5.46 (dd, 1H), 5.12 (s, 0.5H), 4.98 (s, 0.5H),4.13-3.91 (m, 4H), 3.52 (d, 1H), 3.16 (bs, 1H), 2.68 (dd, 1H), 2.17 (dd,1H), 1.45-1.41 (m, 1H), 1.30-1.21 (m, 3H).

Compound 33: MS: m/z 497.0 (M+H)⁺; 1H NMR (CD₃OD) δ7.33 (d, 1H),7.21-7.12 (m, 2H), 7.06-7.0 (m, 2H), 6.79-6.69 (m, 2H), 5.70 (d, 1H),5.61-5.57 (m, 1H), 5.39 (s, 0.5H), 5.27 (s, 0.5H), 4.04 (dd, 1H), 3.86(dd, 1H), 3.43 (d, 1H), 2.74-2.72 (m, 1H), 2.42-2.37 (m, 1H), 1.47-1.45(m, 1H).

Compound 34: MS: m/z 573.1 (M+H)⁺; ¹H NMR (CDCl₃) δ7.50-7.31 (m, 4H),7.22-7.09 (m, 5H), 6.90-6.81 (m, 2H), 6.62-6.60 (m, 1H), 6.19 (d, 1H),5.48 (d, 1H), 5.04 (s, 1H), 4.41-4.29 (m, 2H), 4.11-4.07 (m, 2H),3.63-3.47 (m, 1H), 3.23-3.07 (m, 1H), 2.96 (d, 1H), 2.58 (bs, 1H),2.19-1.97 (m, 1H), 1.72-1.71 (m, 1H), 0.87-0.85 (m, 1H).

Compound 35: MS: m/z. 485.0 (M+H)⁺; 1H NMR (CDCl₃) δ7.23 (d, 1H),7.11-7.05 (m, 1H), 7.00-6.89 (m, 2H), 6.83-6.76 (m, 1H), 6.47 (d, 1H),5.88 (d, 1H), 5.56 (dd, 1H), 5.22 (s, 1H), 4.15 (d, 1H), 4.06 (d, 1H),2.95 (d, 1H), 2.13-2.11 (m, 1H), 2.10-2.09 (m, 1H), 1.06 (d, 3H),0.68-0.64 (m, 1H).

Compound 36: MS: m/z. 481.1 (M+H)⁺; 1H NMR (CDCl₃) δ7.23 (d, 1H),7.08-6.95 (m, 3H), 6.74-6.69 (m, 1H), 6.50 (d, 1H), 5.83 (d, 1H), 5.57(dd, 1H), 5.18 (s, 1H), 4.15 (d, 1H), 4.05 (d, 1H), 2.96 (d, 1H), 2.25(s, 3H), 2.12-2.08 (m, 1H), 2.04-1.94 (m, 1H), 1.05 (d, 3H), 0.68-0.65(m, 1H).

Compound 37: MS: m/z. 481.1 (M+H)⁺; 1H NMR (CDCl₃) δ7.29 (d, 1H),7.11-7.03 (m, 3H), 7.01-6.96 (m, 1H), 6.82-6.78 (m, 1H), 6.62 (d, 1H),5.84 (d, 1H), 5.52 (dd, 1H), 5.17 (s, 1H), 4.08 (d, 2H), 4.04 (d, 1H),2.98 (d, 1H), 2.08-2.05 (m, 1H), 1.94-1.89 (m, 1H), 1.43-1.36 (m, 1H),1.16-1.07 (m, 1H), 1.02-1.97 (m, 3H), 0.67-0.68 (m, 1H).

Compound 38: MS: m/z. 497.1 (M+H)⁺; 1H NMR (CDCl₃) δ7.28 (d, 1H),7.11-7.03 (m, 3H), 6.99-6.95 (m, 1H), 6.82-6.76 (m, 1H), 6.62 (d, 1H),5.84 (d, 1H), 5.52 (dd, 1H), 5.15 (s, 1H), 4.20 (d, 1H), 4.07 (d, 1H),3.64-3.58 (m, 1H), 3.25 (s, 3H), 3.05 (d, 1H), 3.04-2.80 (m, 1H),2.20-2.17 (m, 1H), 2.07-2.01 (m, 1H), 0.91-0.82 (m, 1H).

Compound 39: MS: m/z. 457.1 (M+H)⁺; 1H NMR (CDCl₃) δ 7.27 (d, 1H),7.11-6.97 (m, 2H), 5.84 (d, 1H), 5.50 (dd, 1H), 5.23 (s, 1H), 4.16 (d,1H), 4.05 (d, 1H), 2.92 (d, 1H), 1.93-1.84 (m, 1H), 1.74-1.68 (m, 1H),1.01-0.94 (m, 1H), 0.90-0.83 (m, 1H).

Synthesis and Characterization of Compound 40

Compound 1 (0.033 g, 0.076 mmole) was dissolved in CH₃CN (6 ml), andK₂CO₃ (0.315 g, 2.28 mmole), NaI catalyst and chloromethyl acetate(0.050 g, 0.46 mmole) were added. Then the mixture was stirred at 60° C.for 16 hours. The mixture solution was concentrated under reducedpressure and purified by PLC to afford Compound 40 (6.1 mg, yield: 16%)MS: m/z 507.1 (M+H)⁺; ¹H NMR (CDCl₃) δ7.32-7.04 (m, 6H), 6.89-6.84 (m,1H), 6.76 (d, 1H), 5.98 (d, 1H), 5.92 (d, 1H), 5.80 (d, 1H), 5.44 (dd,1H), 5.18 (s, 1H), 4.12 (d, 1H), 4.06 (d, 1H), 2.91 (d, 1H), 2.14 (s,3H), 1.94-1.90 (m, 1H), 1.50-1.44 (m, 1H), 0.88-0.77 (m, 2H).

Synthesis and Characterization of Compounds 41-61

Each of compounds 41-61 was prepared following the similar protocolsdescribed in the preparation of compound 40.

Analytical data of compounds 41-61 are listed below.

Compound 41: MS: m/z. 552.1 (M+H)⁺; ¹H NMR (CDCl₃) δ7.23 (d, 1H),7.08-7.01 (m, 3H), 6.98-6.90 (m, 1H), 6.72 (d, 1H), 5.97 (d, 1H), 5.48(dd, 1H), 5.16 (s, 1H), 4.20 (d, 1H), 4.04 (d, 1H), 3.60-3.33 (m, 4H),2.90 (d, 1H), 1.93-1.87 (m, 1H), 1.57-1.41 (m, 1H), 1.38-1.28 (m, 6H),0.87-0.74 (m, 2H).

Compound 42: MS: m/z 716.1 (M+H)⁺; ¹H NMR (CDCl₃) δ7.36-7.26 (m, 4H),7.20-6.97 (m, 6H), 6.88-6.27 (m, 2H), 6.28 (d, 0.5H), 6.15 (d, 0.5H),6.00-5.95 (m, 1H), 5.87 (d, 0.5H), 5.74 (d, 0.5H), 5.48-5.43 (m, 1.5H),5.24-5.10 (m, 2.5H), 5.01 (d, 0.5H), 4.75 (d, 0.5H), 4.54-4.49 (m,0.5H), 4.36-4.31 (m, 0.5H), 4.11-4.00 (m, 2H), 2.88-2.82 (m, 1H),2.50-2.47 (m, 0.5H), 2.24-2.17 (m, 0.5H), 2.00-1.98 (m, 0.5H), 1.90-1.85(m, 0.5H), 1.46-1.39 (m, 1H), 1.05-0.68 (m, 8H).

Compound 43: MS: m/z 579.1 (M+H)⁺; ¹H NMR (CDCl₃) δ7.28 (d, 1H),7.09-7.05 (m, 3H), 7.02-6.95 (m, 1H), 6.91-6.89 (m, 1H), 6.81-6.74 (m,1H), 5.99 (d, 01H), 5.48 (dd, 1H), 5.16 (s, 1H), 4.16 (d, 1H), 4.04 (d,1H), 2.91 (d, 1H), 2.71-2.66 (m, 2H), 1.92-1.88 (m, 1H), 1.83-1.71 (m,2H), 1.70-1.59 (m, 2H), 1.65-1.50 (m, 1H), 1.47-1.34 (m, 6H), 0.97-0.77(m, 5H).

Compound 44: MS: m/z 543.1 (M+H)⁺; 1H NMR (CDCl₃) δ7.50-7.47 (m, 2H),7.36-7.21 (m, 4H), 7.07-6.95 (m, 4H), 6.76-6.71 (m, 1H), 6.53 (d, 1H),5.96 (d, 1H), 5.49-5.40 (m, 3H), 5.09 (s, 1H), 4.04-3.95 (m, 2H), 2.83(d, 1H), 1.94-1.89 (m, 1H), 1.39-1.34 (m, 1H), 0.76-0.65 (m, 2H).

Compound 45: MS: m/z 541.0 (M++1); ¹H NMR (CDCl₃) δ7.31 (d, 1H),7.06-7.00 (m, 4H), 6.85-6.84 (m, 1H), 6.73 (d, 1H), 6.03 (d, 1H), 5.96(d, 1H), 5.80 (d, 1H), 5.49 (d, 1H), 5.15 (s, 1H), 4.13 (d, 1H), 4.05(d, 1H), 3.87 (s, 3H), 2.91 (d, 1H), 1.95-1.90 (m, 1H), 1.49-1.48 (m,1H), 0.88-0.76 (m, 2H).

Compound 46: MS: m/z 555.1 (M+H)⁺; 1H NMR (CDCl₃) δ7.23 (d, 0.5H), 7.18(d, 0.5H), 7.14-7.09 (m, 2H), 7.05-6.92 (m, 2H), 6.87-6.84 (m, 0.5H),6.72-6.70 (m, 0.5H), 6.57-6.55 (m, 0.5H), 6.44-6.42 (m, 0.5H), 5.97 (d,0.5H), 5.94 (d, 0.5H), 5.53-5.44 (m, 1H), 5.14 (s, 0.5H), 5.12 (s,0.5H), 4.14-4.09 (m, 1H), 4.06 (d, 0.5H), 4.01 (d, 0.5H), 3.83 (s,1.5H), 3.68 (s, 1.5H), 3.03-2.872 (m, 1H), 1.97-1.91 (m, 1H), 1.80-1.78(m, 3H), 1.47-1.32 (m, 1H), 0.85-0.71 (m, 2H).

Compound 47: MS: m/z 539.1 (M+H)⁺; ¹H NMR (CDCl₃) δ7.22 (d, 1H),7.10-7.01 (m, 3H), 6.79 (t, 1H), 6.62 (d, 1H), 5.96 (d, 1H), 5.91 (d,1H), 5.80 (d, 1H), 5.53 (dd, 1H), 5.17 (s, 1H), 4.13 (d, 1H), 4.12 (d,1H), 2.90 (d, 1H), 2.25 (s, 3H), 2.14 (s, 3H), 1.94-1.89 (m, 1H),1.50-1.43 (m, 1H), 0.85-0.73 (m, 2H).

Compound 48: MS: m/z 538.1 (M+H)⁺; 1H NMR (CDCl₃) δ7.21-7.29 (m, 1H),7.09-6.90 (m, 3H), 6.80-6.59 (m, 2H), 5.97 (d, 1H), 5.51 (d, 1H), 5.20(bs, 1H), 4.19-4.10 (m, 2H), 3.16-2.98 (m, 6H), 2.90 (d, 1H), 2.25 (s,3H), 1.91-1.87 (m, 1H), 1.52 (m, 1H), 0.83-0.73 (m, 2H).

Compound 49: MS: m/z 579.1 (M+H)⁺; 1H NMR (CDCl₃) δ7.29-7.26 (m, 1H),7.07-7.01 (m, 3H), 6.80-6.75 (m, 1H), 6.56 (d, 1H), 5.95 (d, 1H),5.52-5.47 (m, 1H), 5.29 (d, 1H), 5.20-5.16 (m, 2H), 4.17-4.07 (m, 2H),2.95-2.88 (m, 1H), 2.25 (s, 3H), 2.14 (s, 3H), 1.98-1.93 (m, 1H),1.54-1.47 (m, 1H), 0.87-0.74 (m, 2H).

Compound 50: MS: m/z 555.1 (M+H)⁺; 1H NMR (CDCl₃) δ7.28 (d, 1H),7.10-6.97 (m, 3H), 6.77 (t, 1H), 6.60 (d, 1H), 6.06 (d, 1H), 5.96 (d,1H), 5.78 (d, 1H), 5.55-5.50 (m, 1H), 5.18 (s, 1H), 4.16-4.12 (m, 2H),3.87 (s, 3H), 2.92 (d, 1H), 2.25 (s, 3H), 1.95-1.90 (m, 1H), 1.52-1.46(m, 1H), 0.88-0.73 (m, 2H).

Compound 51: MS: m/z 583.1 (M+H)⁺; ¹H NMR (CDCl₃) δ7.28 (d, 1H),7.10-6.91 (m, 3H), 6.78 (t, 1H), 6.69 (d, 1H), 6.11 (d, 1H), 5.96 (d,1H), 5.79 (d, 1H), 5.52 (d, 1H), 5.17 (s, 1H), 5.02-4.94 (m, 1H),4.16-4.12 (m, 2H) 2.92 (d, 1H), 2.25 (s, 3H), 1.91-1.88 (m, 1H),1.44-1.26 (m, 7H), 0.90-0.75 (m, 2H).

Compound 52: MS: m/z 542.8 (M+H)⁺; ¹H NMR (CDCl₃) δ7.23 (d, 1H),7.13-6.85 (m, 4H), 6.61 (d, 1H), 6.00 (d, 1H), 5.93 (d, 1H), 5.77 (d,1H), 5.53 (dd, 1H), 5.21 (s, 1H), 4.15-4.10 (m, 2H), 2.90 (d, 1H), 2.14(s, 3H), 1.95-1.89 (m, 1H), 1.51-1.44 (m, 1H), 0.87-0.71 (m, 2H).

Compound 53: MS: m/z 583.0 (M+H)⁺; 1H NMR (CDCl₃) δ7.28 (d, 1H),7.13-6.83 (m, 4H), 6.55 (d, 1H), 6.01 (d, 1H), 5.50 (dd, 1H), 5.33-5.15(m, 3H), 4.16-4.12 (m, 2H), 2.91 (d, 1H), 2.11 (s, 3H), 1.98-1.93 (m,1H), 1.54-1.47 (m, 1H), 0.82-0.71 (m, 2H).

Compound 54: MS: m/z 559.0 (M+H)⁺; 1H NMR (CDCl₃) δ7.30 (d, 1H),7.14-6.83 (m, 4H), 6.59 (d, 1H), 6.15 (d, 1H), 5.97 (d, 1H), 5.80 (d,1H), 5.53 (dd, 1H), 5.22 (s, 1H), 4.16-4.12 (m, 2H), 3.87 (s, 3H), 2.92(d, 1H), 1.96-1.92 (m, 1H), 1.54-1.47 (m, 1H), 0.88-0.73 (m, 2H).

Compound 55: MS: m/z 493.1 (M+H)⁺; 1H NMR (CDCl₃) δ7.32-7.24 (m, 3H),7.16 (d, 1H), 7.09-7.07 (m, 2H), 6.87-6.78 (m, 2H), 6.01 (d, 1H), 5.72(d, 1H), 5.15 (s, 1H), 4.15 (d, 1H), 3.50 (d, 1H), 2.91 (d, 1H), 2.41(s, 3H), 1.92-1.89 (m, 1H), 1.55-1.52 (m, 1H), 0.90-0.83 (m, 2H).

Compound 56: MS: m/z 525.0 (M+H)⁺; 1H NMR (CDCl3) δ7.24-7.22 (m, 2H),7.23 (d, 1H), 7.06 (dd, 1H), 7.01-6.86 (m, 3H), 6.61 (d, 1H), 6.00 (d,1H), 5.93 (d, 1H), 5.80 (d, 1H), 5.76 (d, 1H), 5.19 (s, 1H), 4.09 (d,1H), 3.58 (d, 1H), 2.88 (d, 1H), 2.14 (s, 3H), 1.96-1.84 (m, 1H),1.49-1.44 (m, 1H), 0.82-0.74 (m, 2H).

Compound 57: MS: m/z 561.1 (M+H)⁺; ¹H NMR (CDCl₃) δ7.29-7.20 (m, 2H),7.04-6.93 (m, 3H), 6.76 (t, 1H), 6.56 (d, 1H), 5.95 (d, 1H), 5.76 (d,1H), 5.31-5.16 (m, 3H), 4.07 (d, 1H), 3.60 (d, 1H), 2.90 (d, 1H), 2.45(s, 3H), 2.15 (s, 3H), 1.98-1.93 (m, 1H), 1.53-1.46 (m, 1H), 0.90-0.71(m, 2H).

Compound 58: MS: m/z 539.1 (M+H)⁺; ¹H NMR (CDCl₃) δ7.31-7.22 (m, 3H),7.15-6.88 (m, 3H), 6.77-6.67 (m, 1H), 6.06 (d, 0.75H), 6.00 (d, 0.25H),5.87-5.80 (m, 2H), 5.43 (d, 0.25H), 5.28 (d, 0.75H), 5.15 (s, 0.25H),5.00 (s, 0.75H), 4.14 (d, 0.75H), 4.05 (d, 0.25H), 3.12-3.06 (m, 1H),2.12 (s, 3H), 1.96-1.89 (m, 1H), 1.59-1.45 (m, 1H), 1.37-1.25 (m, 3H),0.94-0.83 (m, 1H), 0.63-0.48 (m, 1H).

Compound 59: MS: m/z 539.1 (M+H)⁺; 1H NMR (CDCl3) δ7.26 (d, 1H),7.09-7.05 (m, 3H), 7.02-6.97 (m, 1H), 6.90-6.95 (m, 1H), 6.72 (d, 1H),5.94 (d, 1H), 5.87 (d, 1H), 5.79 (d, 1H), 5.52 (dd, 1H), 5.07 (s, 1H),4.14 (d, 1H), 4.05 (d, 1H), 4.02 (d, 1H), 2.92 (d, 1H), 2.14 (s, 3H),2.12-2.10 (m, 1H), 1.76-1.70 (m, 1H), 1.03 (d, 3H), 0.47-0.44 (m, 1H).

Compound 60: MS: m/z. 557.1 (M+H)⁺; 1H NMR (CDCl₃) δ7.22 (d, 1H),7.17-6.97 (m, 2H), 6.93-6.85 (m, 2H), 6.59 (d, 1H), 6.01 (d, 1H), 5.92(d, 1H), 5.68 (d, 1H), 5.55 (dd, 1H), 5.14 (s, 1H), 4.14 (dd, 1H), 4.02(d, 1H), 2.92 (d, 1H), 2.15 (s, 3H), 2.14-2.10 (m, 1H), 1.75-1.68 (m,1H), 1.03 (d, 3H), 0.45-0.43 (m, 1H).

Compound 61: MS: m/z 553.1 (M+H)⁺; 1H NMR (CDCl₃) δ7.23 (d, 1H),7.17-6.97 (m, 3H), 6.82-6.77 (m, 1H), 6.59 (d, 1H), 5.96 (d, 1H), 5.90(d, 1H), 5.79 (d, 1H), 5.70 (dd, 1H), 5.10 (s, 1H), 4.14 (d, 1H), 4.02(d, 1H), 2.93 (d, 1H), 2.25 (s, 3H), 2.14 (s, 3H), 2.13-2.10 (m, 1H),1.75-1.67 (m, 1H), 1.03 (d, 3H), 0.45-0.43 (m, 1H).

Shown in the table below are the structures of compounds 40-61.

Compound 40

Compound 41

Compound 42

Compound 43

Compound 44

Compound 45

Compound 46

Compound 47

Compound 48

Compound 49

Compound 50

Compound 51

Compound 52

Compound 53

Compound 54

Compound 55

Compound 56

Compound 57

Compound 58

Compound 59

Compound 60

Compound 61

Example 2: Cytopathic Effect (CPE) Reduction Assay

A CPE reduction assay was performed as follows to evaluate the potencyof test compounds in inhibiting the activity of influenza viruses.

Confluent MDCK cells in 96-well tissue culture plates were incubatedwith test compounds and influenza A or B viruses at low multiplicity ofinfection for 72 h at 37° C. The plates were fixed by adding 0.5%formaldehyde, followed by staining with 0.5% Crystal Violet.Subsequently, the plates were measured at 570 nm with a microplatereader (Multiskan Ascent, Thermo). The concentration required for a testcompound to to reduce the virus-induced CPE by 50% relative to the viruscontrol was expressed as the 50% effective dose (EC₅₀).

Compounds 1-39 were tested using the CPE reduction assay. For influenzaA virus infection, it was observed that 30 test compounds (i.e.,Compounds 1-10, 13, 16-22, 25, 27-30, 32-33, 35-38 and 39) unexpectedlyexhibited EC₅₀ values lower than 0.1 μM and 9 test compounds (i.e.,Compounds 11-12, 14-15, 23-24, 26, 31, and 34) exhibited EC₅₀ values of0.1-1 μM. On the other hand, for influenza B virus infection, it wasobserved that 15 test compounds (i.e., Compounds 2-5, 7-9, 14-15, 17,24, 35, 37-38 and 39) unexpectedly exhibited EC₅₀ values lower than 0.1μM and 24 test compounds (i.e., Compounds 1, 6, 10-13, 16, 18-23, 25-34,and 36) exhibited EC₅₀ values of 0.1-1 M.

Further, it was observed that compounds of this disclosure containingthe cyclopropyl moiety in Formula (I) unexpectedly exhibited higherpotency in inhibiting the activity of influenza viruses thanstructurally close analogs not containing the cyclopropyl moiety. Theresults of the difference in anti-influenza virus activity between thecomparative compounds (structurally close analogs not containing thecyclopropyl moiety) and the example compounds (containing thecyclopropyl moiety) are shown in the following table.

Activity difference (folds)* Comparative Influenza Influenza compound A₁A₂ A₃ Y₁ X₁ X₂ X₃ X₄ R Compare with A virus B virus A1 CH N CH₂ S H F HH

Compound 1 2.2 — A2 CH N CH₂ S H F H H

Compound 1 6.6 2.2 A3 CH N CH₂ S H F H H

Compound 1 5.0 — A4 CH N CH₂ S H F H H

Compound 1 15.3 2.5 A5 CH N CH₂ S H F H H

Compound 1 4.6 2.9 B1 CH N CH₂ S F F H H

Compound 2 7.2 3.0 B2 CH N CH₂ S F F H H

Compound 2 3.9 3.3 B3 CH N CH₂ S F F H H

Compound 2 57.9 — B4 CH N CH₂ S F F H H

Compound 2 8.0 4.4 C1 CH N CH₂ S F H Cl H

Compound 3 2.0 — C2 CH N CH₂ S F H Cl H

Compound 3 4.8 — C3 CH N CH₂ S F H Cl H

Compound 3 9.4 3.0 C4 CH N CH₂ S F H Cl H

Compound 3 37.1 8.0 C5 CH N CH₂ S F H Cl H

Compound 3 17.9 2.7 D1 CH N CH₂ S Cl H H H

Compound 4 5.4 — D2 CH N CH₂ S Cl H H H

Compound 4 3.8 — D3 CH N CH₂ S Cl H H H

Compound 4 5.6 2.5 D4 CH N CH₂ S Cl H H H

Compound 4 10.1 5.8 D5 CH N CH₂ S Cl H H H

Compound 4 10.3 8.4 E1 CH N CH₂ S Cl H CH₃ H

Compound 6 2.4 — E2 CH N CH₂ S Cl H CH₃ H

Compound 6 9.2 1.9 E3 CH N CH₂ S Cl H CH₃ H

Compound 6 3.8 — F1 CH N CH₂ S F H CH₃ H

Compound 7 4.6 2.6 F2 CH N CH₂ S F H CH₃ H

Compound 7 4.1 2.1 F3 CH N CH₂ S F H CH₃ H

Compound 7 16.0 3.8 F4 CH N CH₂ S F H CH₃ H

Compound 7 30.0 10.8 F5 CH N CH₂ S F H CH₃ H

Compound 7 27.1 5.5 G1 CH N CH₂ S F H H H

Compound 8 6.8 2.6 G2 CH N CH₂ S F H H H

Compound 8 5.0 2.4 G3 CH N CH₂ S F H H H

Compound 8 5.0 3.3 H1 CH N CH₂ S H H F H

Compound 9 4.7 2.9 H2 CH N CH₂ S H H F H

Compound 9 8.9 2.9 H3 CH N CH₂ S H H F H

Compound 9 27.7 10.4 H4 CH N CH₂ S H H F H

Compound 9 5.4 3.1 I1 CH N CH₂ S H H CH₃ H

Compound 11 3.1 — J1 CH N CH₂ S Cl H F H

Compound 14 4.5 — J2 CH N CH₂ S Cl H F H

Compound 14 3.2 — J3 CH N CH₂ S Cl H F H

Compound 14 4.9 5.1 K1 CH N CH₂ O F H Cl H

Compound 15 3.2 2.9 K2 CH N CH₂ O F H Cl H

Compound 15 8.0 2.1 L1 CH N CH₂ S F F CH₃ H

Compound 16 15.4 3.5 L2 CH N CH₂ S F F CH₃ H

Compound 16 16.7 27.9 M1 CH N CH₂ S F F F H

Compound 17 94.4 13.6 M2 CH N CH₂ S F F F H

Compound 17 4.9 — N1 CH N CH₂ S Cl F H H

Compound 19 3.1 — N2 CH N CH₂ S Cl F H H

Compound 19 3.6 — O1 CH N CH₂ S Cl F F H

Compound 24 3.9 — *Activity difference = (EC₅₀ value of a comparativecompound)/(EC₅₀ value of an example compound)

These results indicate that the compounds of this disclosureunexpectedly exhibited higher potency in inhibiting the activity ofinfluenza viruses, as compared to their structurally close analogs.

Example 3: Survival Rate of Influenza Virus 24 Hours Post-Infection

Tests were performed as follows to evaluate the effect of compounds ofFormula (I) on the survival rates of mice 24 hours post-infection in aninfluenza A mouse model.

Mice were first infected with 100 or 500 pfu/mouse influenza A virus,followed by dosing of compounds of formula (I) 24 hours post-infection.The dosing was administered twice daily for 5 days. Each compound wasorally administered to mice at a dosage of 5, 10, or 20 mg/kg. Miceinfected with 100 or 500 pfu/mouse demonstrated extremely highmortality. Unexpectedly, it was observed that mice treated withcompounds of Formula (I), e.g., Compound 1 and Compound 2, exhibitedsurvival rates of 80-100%, as compared to a survival rate of 16.7%exhibited by mice treated with oseltamivir and a survival rate of 14.3%exhibited by mice treated with comparative compound B 1. Note thatoseltamivir is a commercial drug for treating influenza, and comparativecompound B 1 is a structurally close analog of Compound 2.

These results indicate that compounds of Formula (I) unexpectedlyexhibited high efficacy in treating influenza.

Other Embodiments

All of the features disclosed in this specification may be combined inany combination. Each feature disclosed in this specification may bereplaced by an alternative feature serving the same, equivalent orsimilar purpose. Thus, unless expressly stated otherwise, each featuredisclosed is only an example of a series of equivalent or similarfeatures.

From the above description, one skilled in the art can easily ascertainthe characteristics of the present disclosure, and without departingfrom the spirit and scope thereof, can make various changes andmodifications of the disclosure to adapt it to various usage andconditions. Thus, other embodiments are also within the scope of thefollowing claims.

What is claimed is:
 1. A compound of Formula (I) below, or apharmaceutically acceptable salt, metabolite, or prodrug thereof,

wherein: R₁ is hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl,amino, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆alkylamine, C₃₋₂₀ carbocyclyl, or C₃₋₂₀ heterocyclyl; each of R₂, R₂′,R₃, and R₃′, independently, is hydrogen, deuterium, halogen, cyano,hydroxyl, carboxyl, amino, formyl, nitro, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₂₋₆ alkenyloxy, C₁₋₆ alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆ alkylamine, C₃₋₂₀ carbocyclyl, or C₃₋₂₀heterocyclyl; A₁ is CR₄ or N; A₂ is CR₅R₆ or NR₇; A₃ is CR₅′R₆′ or NR₇′;R₄ is hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, amino,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₃₋₂₀ carbocyclyl,or C₃₋₂₀ heterocyclyl; and each of R₅, R₅′, R₆, R₆′, R₇, and R₇′,independently, is hydrogen, deuterium, halogen, cyano, hydroxyl,carboxyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₃₋₂₀carbocyclyl, or C₃₋₂₀ heterocyclyl; or R₅ and R₆, R₅′ and R₆′, or R₅ andR₅′, together with the adjacent atom to which they are each attached,form C₃₋₁₀ carbocyclyl or C₃₋₁₀ heterocyclyl, wherein each of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₂₋₆ alkenyloxy, C₁₋₆alkylcarbonyl, C₁₋₆ alkyloxycarbonyl, C₁₋₆ alkylamine, C₃₋₁₀carbocyclyl, C₃₋₁₀ heterocyclyl, C₃₋₂₀ carbocyclyl, and C₃₋₂₀heterocyclyl is optionally substituted with 1 to 5 moieties ofdeuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₁₋₆ alkyl(C₃₋₁₀ carbocyclyl), C₁₋₆alkyl(C₃₋₁₀ heterocyclyl), C₁₋₆ alkoxy(C₃₋₁₀ carbocyclyl), C₁₋₆alkoxy(C₃₋₁₀ heterocyclyl), C₃₋₁₀ carbocyclyl, or C₃₋₁₀ heterocyclyl. 2.The compound, or the pharmaceutically acceptable salt, metabolite, orprodrug of claim 1, wherein R₁ is hydrogen, deuterium, halogen,hydroxyl, C₁₋₆ alkyl, or C₁₋₆ alkoxy, and each of R₂, R₂′, R₃, and R₃′,independently, is hydrogen, deuterium, halogen, hydroxyl, carboxyl,amino, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkylcarbonyl, C₁₋₆alkyloxycarbonyl, or C₃₋₂₀ carbocyclyl.
 3. The compound, or thepharmaceutically acceptable salt, metabolite, or prodrug of claim 1,wherein R₁ is hydrogen, deuterium or C₁₋₆ alkyl, and each of R₂, R₂′,R₃, and R₃′, independently, is hydrogen, deuterium, halogen, carboxyl,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylcarbonyl, or C₁₋₆ alkyloxycarbonyl.4. The compound, or the pharmaceutically acceptable salt, metabolite, orprodrug of claim 1, wherein each of R₄, R₅, R₅′, R₆, and R₆′,independently, is hydrogen, deuterium, halogen, hydroxyl, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₃₋₂₀ carbocyclyl, or C₃₋₂₀ heterocyclyl, andeach of R₇ and R₇′, independently, is C₁₋₆ alkyl, C₃₋₂₀ carbocyclyl, orC₃₋₂₀ heterocyclyl, and each of C₁₋₆ alkyl, C₃₋₂₀ carbocyclyl, and C₃₋₂₀heterocyclyl is optionally substituted with 1 to 3 C₃₋₈ carbocyclyl orC₃₋₈ heterocyclyl.
 5. The compound, or the pharmaceutically acceptablesalt, metabolite, or prodrug of claim 4, wherein each of R₇ and R₇′,independently, is

wherein: each of W₁ and W₂, independently, is C₃₋₈ carbocyclyl or C₃₋₈heterocyclyl; Y is O, S, SO, SO₂, or CH₂; R₈ is hydrogen, deuterium,halogen, hydroxyl, C₁₋₆ alkyl, or C₁₋₆ alkoxy, wherein C₁₋₆ alkyl orC₁₋₆ alkoxy is optionally substituted with 1 to 5 deuterium, halogen orhydroxyl groups; m is an integer of 1 to 5; n is an integer of 0 to 2; pis an integer of 0 to 2; and the star (*) indicates a chiral center. 6.The compound, or the pharmaceutically acceptable salt, metabolite, orprodrug of claim 5, wherein each of R₇ and R₇′, independently, is

and wherein m is 1, 2, or
 3. 7. The compound, or the pharmaceuticallyacceptable salt, metabolite, or prodrug of claim 6, wherein each of R₇and R₇′, independently is

and wherein each of R₁₄, R₁₅ and R₁₆, independently, is hydrogen ordeuterium.
 8. The compound, or the pharmaceutically acceptable salt,metabolite, or prodrug of claim 1, wherein: R₁ is hydrogen, deuterium,halogen, or C₁₋₆ alkyl; each of R₂, R₂′, R₃, and R₃′, independently, ishydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkyloxycarbonyl, orC₃₋₂₀ carbocyclyl; each of R₄, R₅, R₅′, R₆, and R₆′, independently, ishydrogen, deuterium, halogen, C₁₋₆ alkyl, or C₂₋₆ alkenyl; and each ofR₇ and R₇′, independently, is hydrogen, deuterium, carboxyl, C₁₋₆ alkyl,C₃₋₂₀ carbocyclyl, or C₃₋₂₀ heterocyclyl.
 9. The compound, or thepharmaceutically acceptable salt, metabolite, or prodrug of claim 1,wherein: R₁ is hydrogen, deuterium or C₁₋₆ alkyl; each of R₂, R₂′, R₃,and R₃′, independently, is hydrogen, deuterium, halogen, carboxyl, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylcarbonyl, or C₁₋₆ alkyloxycarbonyl; eachof R₄, R₅, R₅′, R₆, and R₆′, independently, is hydrogen, deuterium, C₁₋₆alkyl, or C₂₋₆ alkenyl; and each of R₇ and R₇′, independently, is

and wherein: each of W₁ and W₂, independently, is C₃₋₈ carbocyclyl orC₃₋₈ heterocyclyl; Y is O or S; R₈ is hydrogen, deuterium, halogen,hydroxyl, C₁₋₆ alkyl, or C₁₋₆ alkoxy, wherein C₁₋₆ alkyl or C₁₋₆ alkoxyis optionally substituted with 1 to 5 deuterium, halogen or hydroxylgroups; m is an integer of 1 to 5; n is an integer of 0 to 2; p is aninteger of 0 to 2; and the star (*) indicates a chiral center.
 10. Thecompound, or the pharmaceutically acceptable salt, metabolite, orprodrug of claim 1, wherein A₁ is CR₄, A₂ is NR₇ and A₃ is CR₅′R₆′. 11.The compound, or the pharmaceutically acceptable salt, metabolite, orprodrug of claim 1, wherein: A₁ is CH; A₂ is NR₇; A₃ is CR₅′R₆′; R₁ ishydrogen, deuterium or C₁₋₆ alkyl; each of R₂, R₂′, R₃, and R₃′,independently, is hydrogen, deuterium, halogen, carboxyl, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ alkylcarbonyl, or C₁₋₆ alkyloxycarbonyl; each of R₅and R₆, independently, is hydrogen, deuterium, C₁₋₆ alkyl, or C₂₋₆alkenyl; R₇ is

and R₈ is hydrogen, deuterium, halogen, hydroxyl, C₁₋₆ alkyl, or C₁₋₆alkoxy, wherein C₁₋₆ alkyl or C₁₋₆ alkoxy is optionally substituted with1 to 5 deuterium, halogen or hydroxyl groups.
 12. The compound, or thepharmaceutically acceptable salt, metabolite, or prodrug of claim 1,wherein the compound is one of the following compounds:


13. The compound, or the pharmaceutically acceptable salt, metabolite,or prodrug of claim 1, wherein the prodrug has the following formula:

wherein G is —C(R₉R₉′)—O—CO—R₁₀, —C(R₉R₉′)—O—CO—O—R₁₀,—C(R₉R₉′)—NR₁₁—C(═O)—CO—O—R₁₀, —C(R₉R₉′)—O—CO—C(R₉R₉′)—NR₁₁—CO—O—R₁₀,—C(R₉R₉′)—C(R₉R₉′)—O—CO—CO—R₁₀, —C(R₉R₉′)—R₁₀, —C(═O)—O—R₁₀, —C(═O)—R₁₀,—C(═O)—O-alkylene-O—R₁₀, —C(═O)—NR₁₀R₁₁, or —P(═O)(R₁₂R₁₃), and whereineach of R₉, R₉′, and R₁₁, independently, is hydrogen or C₁₋₈ alkyl; R₁₀is C₁₋₈ alkyl, C₃₋₁₀ carbocyclyl, or C₃₋₁₀ heterocyclyl; R₁₂ is C₁₋₈alkoxy; and R₁₃ is C₁₋₈ alkoxy or C₁₋₈ alkylamine.
 14. The compound, orthe pharmaceutically acceptable salt, metabolite, or prodrug of claim13, wherein G is


15. The compound, or the pharmaceutically acceptable salt, metabolite,or prodrug of claim 13, wherein the prodrug is one of the followingcompounds:


16. A pharmaceutical composition, comprising the compound, or thepharmaceutically acceptable salt, metabolite, or prodrug of claim 1, anda pharmaceutically acceptable carrier thereof.
 17. A method of treatinginfluenza, comprising administering to a subject in need thereof aneffective amount of the compound, or the pharmaceutically acceptablesalt, metabolite, or prodrug of claim
 1. 18. A method of preparing acompound of Formula (I) below, or a pharmaceutically acceptable salt,metabolite, or prodrug thereof,

the method comprising: providing an aldehyde

reacting the aldehyde with a carbonyl compound

to afford a first intermediate

reacting the first intermediate with a hydrazine to afford a secondintermediate

and converting the second intermediate to the compound of Formula (I),or the pharmaceutically acceptable salt, metabolite, or prodrug thereof,wherein: P is a protecting group; A₁ is CR₄; A₂ is NR₇; A₃ is CR₅′R₆′;R₁ is hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, amino,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylamine,C₃₋₂₀ carbocyclyl, or C₃₋₂₀ heterocyclyl; each of R₂, R₂′, R₃, and R₃′,independently, is hydrogen, deuterium, halogen, cyano, hydroxyl,carboxyl, amino, formyl, nitro, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ alkoxy, C₂₋₆ alkenyloxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkyloxycarbonyl,C₁₋₆ alkylamine, C₃₋₂₀ carbocyclyl, or C₃₋₂₀ heterocyclyl; R₄ ishydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, amino, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₃₋₂₀ carbocyclyl, orC₃₋₂₀ heterocyclyl; R₅′ is H; and each of R₆′ and R₇, independently, ishydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₃₋₂₀ carbocyclyl, or C₃₋₂₀heterocyclyl, and wherein each of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₂₋₆ alkenyloxy, C₁₋₆ alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆ alkylamine, C₃₋₂₀ carbocyclyl, and C₃₋₂₀heterocyclyl is optionally substituted with 1 to 5 moieties ofdeuterium, halogen, hydroxyl, cyano, amino, nitro, carboxyl, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₁₋₆ alkyl(C₃₋₁₀ carbocyclyl), C₁₋₆alkyl(C₃₋₁₀ heterocyclyl), C₁₋₆ alkoxy(C₃₋₁₀ carbocyclyl), C₁₋₆alkoxy(C₃₋₁₀ heterocyclyl), C₃₋₁₀ carbocyclyl, or C₃₋₁₀ heterocyclyl.